We have previously shown that certain inactivated viruses, including strains of Epstein-Barr virus (EBV), can stimulate human monocyte/macrophages (MO) to secrete monokines capable of upregulating human immunodeficiency virus (HIV) expression in chronically infected human cells. Our current objective was to focus on EBV proteins to determine whether natural proteins affinity purified using specific monoclonal antibodies, are responsible for the monocyte stimulation leading to this effect. Monokine secretion has been determined in response to the EBV gp350 envelope protein, the gp125 viral capsid protein, the p50 early antigen (diffuse distribution), and the p17 early antigen (restricted distribution). Both gp350 and gp125 are capable of stimulating the secretion of monokines which upregulate HIV expression, while data using p50 and p17 are relatively inconsistent. Monokine secretion caused by the EBV glycoproteins is not attributable to contaminating endotoxin. This suggests that some, but not all, EBV proteins may indirectly affect the expression of HIV during the course of an HIV infection by stimulating monokine production. Whether this is a receptor-mediated phenomenon or whether glycosylation is involved in this response is currently under investigation.